Extension Study (CRAD001A1202E1): Until 24 months after renal transplantation, the study was designed to evaluate the long-term safety and efficacy comparing concentration-controlled everolimus with reduced dose cyclosporine (Neoral®) and corticosteroids versus mycophenolate mofetil with standard dose Neoral® and corticosteroids in de novo renal transplant recipients. Beyond 24 months after renal transplantation, the study was designed to provide everolimus treatment for patients in everolimus group until everolimus is approved and marketed in Japan.

The composite efficacy endpoint consisted of treated biopsy proven acute rejection (BPAR) episodes, graft loss, death or loss to follow-up. A treated BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III and which was treated with anti-rejection therapy. The allograft was presumed to be lost on the day the patient starts dialysis and was not able to stop dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was considered as the day of graft loss.

For the individual components (including loss of follow-up)of the composite endpoint, patients are counted for the first event to occur.

Core Study: Number Participants With Combined Graft Loss, Death or Loss to Follow-up [ Time Frame: 12 months ] [ Designated as safety issue: No ]

The allograft was presumed to be lost on the day the patient starts dialysis and was not able to stop dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was considered as the day of graft loss.

A loss to follow-up in graft loss, death or loss to follow-up is a patient who did not experience graft loss or death and whose last day of contact was prior to Day 316, i.e. prior to the Month 12 visit window.

Blood was collected at all visits after Day 3 for trough (collected 5 minutes before study drug dose) everolimus levels and was analyzed at a central laboratory using liquid chromatography mass spectrometry.

An initial everolimus dose of 0.75 mg orally twice daily (1.5 mg/day) was administered 24-36 hours from reperfusion after transplantation and dose adjustments based on everolimus trough level (target trough level 3-8 ng/mL). Reduced dose of cyclosporine was initiated either pre-transplantation or within 24 hours after transplantation following the local regimen. Patients were treated with antibody induction therapy using 20 mg basiliximab two hours prior to transplant and 20 mg basiliximab 4 days post transplant or according to local practice. Corticosteroids were administered according to local practice. Patients were treated for 12 months in the core study and 12 months in the extension study. Everolimus was available after 24 months for compassionate use.

Drug: Everolimus

0.75 mg twice daily, trough level adjusting between 3 and 8 ng/ml.

Other Name: Certican

Drug: Basiliximab

Patients received first dose of basiliximab (20 mg) 2 hours prior to transplantation and 20 mg at Day 4 or according to local practice

Drug: Cyclosporine A

The cyclosporine was initiated either pre-transplant or within 24 hours after transplantation following local regime. Standard dose of cyclosporine was administered with MMF. The Reduced dose of cyclosporine was administered with everolimus.

Other Name: Neoral®

Drug: Corticosteroid

Corticosteroid was administered according to local practice during the trial but at a dose not less than 5mg per day for 12 months of the study

Patients were treated with 1 gram twice a day (2 grams/day) of Mycophenolate mofetil (MMF) and standard dose of cyclosporine for 12 months post renal transplant. Patients were treated with antibody induction therapy using 20 mg basiliximab two hours prior to transplant and 20 mg basiliximab 4 days post transplant or according to local practice. Corticosteroids were administered according to local practice. Patients were treated for 12 months in the core study and 12 months in the extension study.

Drug: Mycophenolate mofetil (MMF)

The initial dose of 2 gm/day Mycophenolate mofetil was started within 24-36 hours from reperfusion after transplantation. MMF was administered daily for 12 months in the core study and 12 months in the extension study.

Other Name: MMF

Drug: Basiliximab

Patients received first dose of basiliximab (20 mg) 2 hours prior to transplantation and 20 mg at Day 4 or according to local practice

Drug: Cyclosporine A

The cyclosporine was initiated either pre-transplant or within 24 hours after transplantation following local regime. Standard dose of cyclosporine was administered with MMF. The Reduced dose of cyclosporine was administered with everolimus.

Other Name: Neoral®

Drug: Corticosteroid

Corticosteroid was administered according to local practice during the trial but at a dose not less than 5mg per day for 12 months of the study

Eligibility

Ages Eligible for Study:

18 Years to 65 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Core Study Inclusion Criteria:

Male or female de novo renal transplant recipients between 18 and 65 years of age

Patients who have tested positive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or Hepatitis B surface antigen. Laboratory results obtained within 6 months prior to randomization are acceptable, otherwise these tests should be performed within two weeks prior to randomization.

Recipients of organs from donors who test positive for Hepatitis B surface antigen, HCV or HIV are excluded

Donor organ with a cold ischemia time >24 hours

Donor age greater than 65 years

Patients with platelet count <100,000/mm at baseline before transplantation

Patients with an absolute neutrophil count of < 1,500/mm³ or white blood cell count of < 4,500/mm³ at baseline before transplantation

Patients who have an abnormal liver profile such as alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alkaline phosphatase (ALP) or total bilirubin >3 times the upper limit of normal (ULN)

Patients with a known hypersensitivity to either of the study drugs or their class, or to any of the excipients

Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450

Patients who are unable to take oral medication at time of randomization

Patients who received an investigational drug or who have been treated with a non-protocol immunosuppressive drug or treatment within 30 days or 5 half-lives prior to randomization

Patients with a history of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized excised non-melanomatous skin lesions

Patients with clinically significant systemic infection at time of transplant or within two weeks prior to transplant

Patients with a history of severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus

Patients who have cardiac failure at time of screening (resting dyspnea, with Grade ≥ 3 according to Old New York Heart Association Classification (Appendix 7) or any severe cardiac disease as determined by the investigator

Patients who have any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study medication

Patients with abnormal physical or laboratory findings of clinical significance within 2 weeks prior to randomization which would interfere with the objectives of the study

Patients with any history of coagulopathy or medical condition requiring long-term anticoagulation which would preclude renal biopsy after transplantation. (Low dose aspirin treatment or interruption of chronic anticoagulant is allowed)

Females of childbearing potential who are planning to become pregnant, who are pregnant and/or lactating, who are unwilling to use effective means of contraception.

Patients who had given written informed consent to participate in this extension study

Extension Study Exclusion Criteria:

Women of childbearing potential who were planning to become pregnant, who were unwilling to use two or more effective means of contraception, including abstinence judged by the investigator, surgical sterilization (e.g. bilateral tubal ligation, hysterectomy), hormonal contraception (implantable, patch, oral), and barrier methods (male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal were not acceptable methods of contraception.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00658320